Abstract
Glucocorticoids are very effective anti-inflammatory drugs and widely used for inflammatory bowel disease (IBD) patients. However, approximately 20% of IBD patients do not respond to glucocorticoids and the reason for this is largely unknown. Dietary advanced glycation endproducts (AGEs) are formed via the Maillard reaction during the thermal processing of food products and can induce a pro-inflammatory reaction in human cells. To investigate whether this pro-inflammatory response could be mitigated by glucocorticoids, human macrophage-like cells were exposed to both LPS and AGEs to induce interleukin-8 (IL8) secretion. This pro-inflammatory response was then modulated by adding pharmacological compounds interfering in different steps of the anti-inflammatory mechanism of glucocorticoids: rapamycin, quercetin, and theophylline. Additionally, intracellular reactive oxygen species (ROS) were measured and the glucocorticoid receptor phosphorylation state was assessed. The results show that AGEs induced glucocorticoid resistance, which could be mitigated by quercetin and rapamycin. No change in the phosphorylation state of the glucocorticoid receptor was observed. Additionally, intracellular ROS formation was induced by AGEs, which was mitigated by quercetin. This suggests that AGE-induced ROS is an underlying mechanism to AGE-induced glucocorticoid resistance. This study shows for the first time the phenomenon of dietary AGE-induced glucocorticoid resistance due to the formation of ROS. Our findings indicate that food products with a high inflammatory potential can induce glucocorticoid resistance; these results may be of great importance to IBD patients suffering from glucocorticoid resistance.
Highlights
The use of glucocorticoids is increasing due to the increased prevalence of chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel diseases (IBD)
Differentiated THP-1 cells were exposed to different concentrations of LPS and advanced glycation endproducts (AGEs) for 24 h, after which IL8 secretion was assessed by ELISA and cell viability was assessed by MTT
To determine the anti-inflammatory effect of corticosteroids on both AGE- and LPS-induced inflammation, cells were exposed in an additional experiment to different concentrations of cortisol in combination with 10%
Summary
The use of glucocorticoids is increasing due to the increased prevalence of chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel diseases (IBD). GR homodimerizes and binds to glucocorticoid responsive elements (GRE) in the promotor region of glucocorticoid responsive genes, thereby switching on anti-inflammatory genes [5]. These genes include genes encoding for β2 adrenergic receptors and mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1), which inhibits MAP kinases and thereby switches off pro-inflammatory gene expression [6,7]. Glucocorticoids can directly enhance the degradation of the mRNA of pro-inflammatory genes, such as that of tumor necrosis factor (TNF)-alpha [8,9]
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